How lung specific transcription factors interact with chromatin remodeling factors to regulate the lung epigenome in both the developing and repairing adult lung is poorly understood. Our previous work has identified the Foxp1/2/4 family of forkhead transcription factors as critical regulators of lung gene transcription. We have recently demonstrated that Foxp1/2/4 physically interact with components of the NuRD chromatin remodeling complex to control lung epithelial gene transcription and the injury response after hyperoxic lung injury. The NuRD complex contains histone deacetylases 1 and 2 (Hdac1 and Hdac2) as its core deacetylase activity. Hdacs function by acetylating histones which causes a relaxation of chromatin structure and increased transcriptional activity. Hdacs can also deacetylate other proteins including transcription factors. Hdac function is counterbalanced by acetylatransferases including p300 and CBP. We have begun to explore the importance of Hdac mediated chromatin remodeling complexes by inactivating Hdac1 and Hdac2 in the developing and adult lung epithelium. Complete loss of Hdac1/2 causes severe defects in early proximal airway epithelial development including decreased maintenance of Sox2+ proximal progenitors accompanied by an increase in apoptosis. A loss of Foxp1 and Foxp4, which interact with Hdac1/2 containing complexes, also results in severe defects in proximal airway epithelial development. Sox2+ proximal progenitors are specified normally in Foxp1/4 DKO mutants but their ability to differentiate into secretory and neuroendocrine cell lineages in the proximal airways is severely compromised. Both microarray and ChIP-seq analysis demonstrates that Foxp1 and Foxp4 regulate a critical network of genes required for secretory cell differentiation in proximal airway epithelium, in particular SPDEF, a master regulator of the goblet cell lineage. The similarities in phenotypes between Hdac1/2 and Foxp1/4 mutants along with the biochemical interaction between these factors suggests that Foxp1/4 function is regulated, at least in part, through interactions with Hdac1/2 containing chromatin remodeling complexes and that together these factors orchestrate proximal airway epithelial differentiation and regeneration. Given the reported association between Hdac2 and COPD as well as the fact that many of the genes regulated by Foxp1/4 are also associated with asthma, COPD, or lung cancer, a better understanding of how Foxp1/2/4 and Hdac1/2 functionally interact to regulate differentiation and regeneration of the secretory cell lineage in the lung will provide important insight into multiple human lung diseases.